Synaptic activity and strength are reflected by changes in the post-synaptic secretory pathway

Abstract

Neurons are highly asymmetric cells that span long distances and need to react promptly to local demands. Consequently, neuronal secretory pathway elements are distributed throughout neurites, specifically in post-synaptic compartments, to enable local protein synthesis and delivery. Whether and how changes in local synaptic activity correlate to post-synaptic secretory elements is still unclear. To assess this, we used STED nanoscopy and automated quantitative image analysis of post-synaptic markers of the endoplasmic reticulum, ER-Golgi intermediate compartment, trans-Golgi network, and spine apparatus. We found that the distribution of these proteins was dependent on pre-synaptic activity, measured as the amount of recycling vesicles. Moreover, their abundance correlated to both pre- and post-synaptic markers of synaptic strength. Overall, the results suggest that in small, low-activity synapses the secretory pathway components are tightly clustered in the synaptic area, presumably to enable rapid local responses, while bigger synapses utilise secretory machinery components from larger, more diffuse areas.

Psilocybin Combines Rapid Synaptogenic And Anti-Inflammatory Effects In Vitro

“…Interestingly, at the 72 h timepoint where the most puncta were observed, we did not observe increased intensity (Fig. 3b), perhaps indicating less functional/active 51 or dormant synapses 52 . Representative Airyscan images of dendrites at 3 h, 72 h and controls are illustrated in Fig.…”

“…Psilocybin is currently investigated as an adjuvant therapy to other modes of treatment, and by nding the optimal timing between psilocybin treatment, and for instance therapy, the effect might be even larger. Increased uorescent intensity levels of synaptic puncta expression have previously been correlated to increased levels of functional synapses 50 as well as post-synaptic machinery necessary for active synapses 51 . Intensity levels of Homer1, Piccolo, and Synapsin-1 puncta mirror the increased numbers of puncta we observe, with the exception of 72 h post-psilocybin treatment for Synapsin-1.…”

“…1 h p = .000008698, 3 h p = .000007855, 6 h p = .000008931) intensity at 1 and 3 h post-psilocybin treatment, followed by a reduction at 6 h. For both Piccolo and Homer1, the expression levels per puncta normalized to baseline at the 24 h timepoint. Previous studies have correlated increased synaptic protein uorescence to increased functional synapses 50 and increased post-synaptic secretory protein pathways 51 . One possible confounding factor could be discrepancies in detection of puncta with high protein expression compared to dimmer puncta.…”

The Synaptic Extracellular Matrix: Long-Lived, Stable, and Still Remarkably Dynamic

“…The authors further established this link at the synapses themselves. To do so, they labeled actively recycling synaptic vesicles using antibodies against the lumenal domain of synaptotagmin1 (Syt1) as a proxy for local synaptic activity (Kraszewski et al, 1996 ; Wilhelm et al, 2010 ; Truckenbrodt et al, 2018 ; Gürth et al, 2020 ). Using stimulated emission depletion (STED) microscopy, they confirmed that local synaptic activity is significantly correlated to the extent of recycling.…”

“…While this is the only demonstration, to our knowledge, of a complete recycling loop of an ECM molecule, many additional studies also add credence to the concept of ECM recycling at synapses. These include reports of ECM molecules that undergo internalization (e.g., Coopman et al, 1996 ; Tammi et al, 2001 ; Shi and Sottile, 2008 ; Lobert et al, 2010 ; Leonoudakis et al, 2014 ), demonstrations that ECM receptors are present at synapses (e.g., Kramár et al, 2002 ; Huang et al, 2006 ; Roszkowska et al, 2016 ; Izumi et al, 2017 ; Apóstolo et al, 2020 ; Briatore et al, 2020 ), and reports that synapses contain the machinery for trafficking recycling molecules in an activity-dependent manner (Tang, 2008 ; Gürth et al, 2020 ; Helm et al, 2021 ). Nevertheless, additional demonstrations of the recycling of ECM molecules in neurons are anticipated in the future.…”